This invention relates to novel ester derivatives of prostaglandin E.sub.2 (hereinafter identified as "PGE.sub.2 "), PGE.sub.1, and 13,14-dihydro-PGE.sub.1 and their 15-methyl, 16-(or 16,16-di-)-methyl, and phenyl-substituted analogs, including the respective 15(R)epimers, and to processes for producing them.
PGE.sub.2 is represented by the formula: ##SPC2##
A systematic name for PGE.sub.2 is 7-{3.alpha.-hydroxy-2.beta.-[ (3S)-3-hydroxy-trans-1-octenyl]-5-oxo-1.alpha. -cyclopentyl}-cis-5-heptenoic acid. PGE.sub.2 is known to be useful for a variety of pharmacological and medical purposes, for example labor induction and abortion in pregnant animals, including humans, menstrual regulation in both pregnant and non-pregnant animals, including humans, reduction and control of gastric secretion, and as a hypotensive agent to reduce blood pressure in mammals, including humans. See Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and references cited therein. As to racemic PGE.sub.2, see for example W. P. Schneider, Chem. Commun. 304 (1969).
The 15(S)-15-methyl-PGE.sub.2 analog and its 15(R) epimer are represented by the formula: ##SPC3##
Wherein M' is ##EQU5## following the usual convention wherein broken line attachment of hydroxy to the side chain at carbon 15 indicates the natural or S configuration and solid line attachment of hydroxy indicates the epi or R configuration. See for example Nugteren et al., Nature 212, 38 (1966) and Cahn, J. Chem. Ed. 41, 116 (1964). The 15(S)-15-methyl- and 15(R)-15-methyl-PGE.sub.2 analogs in their optically active and racemic forms are known. See for example U.S. Pat. No. 3,728,382. These analogs are also useful for the above-described pharmacological purposes.
The 16-(or 16,16-di)methyl-PGE.sub.2 analogs and their 15(R) epimers are represented by the formula: ##SPC4##
wherein M is ##EQU6## wherein R.sub.3 is hydrogen or methyl, and wherein each of R.sub.4 and R.sub.5 is hydrogen or methyl, being the same or different. These 16-methyl- and 16,16-dimethyl-PGE.sub.2 analogs and their 15(R) epimers in their optically active and racemic forms are available or can be prepared by methods known in the art. See for example German Pat. No. 2,217,044, Derwent Farmdoc No. 71483T.
The phenyl-substituted PGE.sub.2 analogs and their 15(R) epimers are represented by the formula: ##SPC5##
wherein M is ##EQU7## wherein R.sub.3 is hydrogen or methyl, and wherein C.sub.t H.sub.2t represents a valence bond or alkylene of one to 10 carbon atoms, inclusive, with one to 7 carbon atoms, inclusive, between ##EQU8## and the phenyl ring. These substituted analogs and their 15(R) epimers in their optically active and racemic forms are available or can be prepared by methods known in the art. See for example German Pat. No. 2,154,309, Derwent Farmdoc No. 31279T.
PGE.sub.1 is represented by the formula: ##SPC6##
and the PGE.sub.1 analogs are represented similarly to the PGE.sub.2 analogs above except that cis-CH=CH- in the carboxy acid side chain of formulas II, III, and IV is replaced by --CH.sub.2 CH.sub.2 -. These PGE.sub.1 compounds are available or are prepared by methods known in the art. See for example E. J. Corey et al., J. Am. Chem. Soc. 90, 3245 (1968) and 92, 2586 (1970); U.S. Pat. Nos. 3,069,322, and 3,728,382; 3,598,858, J. E. Pike et al., J. Org. Chem. 34, 3552 (1969); G. L. Bundy et al., Ann. N.Y. Acad. Sci. 180, 76 (1971); and German Pat. No. 2,154,309, Derwent Farmdoc No. 31279T.
13,14-Dihydro-PGE.sub.1 is represented by the formula: ##SPC7##
and the 13,14-dihydro-PGE.sub.1 analogs are represented similarly to the PGE.sub.2 analogs above except that cis--CH=CH-- in the carboxy acid side chain and trans--CH=CH-- in the alkyl-terminated side chain of formulas II, III, and IV are replaced by --CH.sub.2 CH.sub.2 --. These 13,14-dihydro-PGE.sub.1 compounds are available or are prepared by methods known in the art. See for example U.S. Pat. Nos. 3,711,528, 3,728,382, 3,776,938; and German Pat. No. 2,154,309, Derwent Farmdoc No. 31279T.
All of the above prostaglandin-type compounds are known to be useful for a variety of pharmacological and medical purposes, and the esters of this invention are useful for the same purposes.
Esters of the above compounds are known, wherein the hydrogen atom of the carboxyl group is replaced by a hydrocarbyl or substituted hydrocarbyl group. Among these are the methyl ester of PGE.sub.2 (B. Samuelsson, J. Biol. Chem. 238, 3229 (1963)), the methyl ester of 15-methyl-PGE.sub.2 (E. W. Yankee et al., J. Am. Chem. Soc. 94, 3651 (1972)), the methyl ester of 13,14-dihydro-PGE.sub.1 (U.S. Pat. No. 3,598,858), the decyl ester of PGE.sub.2 (Belgian Pat. No. 765,732, Derwent Farmdoc No. 67580S), the 2-phenoxyethyl ester of PGE.sub.2 (Belgian Pat. No. 776,294, Derwent Farmdoc No. 39011T), the phenyl and alkyl-phenyl esters of PGE.sub.2 (British Spec. 1,282,661, Derwent Farmdoc No. 67438R), the p-(1,1-3,3-tetramethyl-butyl)-phenyl ester of PGE.sub.2, the .alpha. (and .beta.-)-naphthyl ester of PGE.sub.2, and the 5,6,7,8-tetrahydro-2-naphthyl ester of PGE.sub.2 (Belgian Pat. No. 775,106, Derwent Farmdoc No. 33705T) the methyl ester of 16,16-dimethyl-PGE.sub.2 (German Pat. No. 2,217,044, Derwent 71483T), and the methyl and phenyl esters of 17-phenyl-18,19,20-trinor-PGE.sub.2 (German Pat. No. 2,154,309, Derwent 31279T).